Antibiotic compositions

ABSTRACT

The invention provides an antibiotic composition comprising coated micropellets and a method for preparing said antibiotic composition.

FIELD OF THE INVENTION

The present invention provides an antibiotic composition comprisingcoated micropellets.

BACKGROUND OF THE INVENTION

Antibiotics such as clarithromycin and erythromycin has been used in thetreatment of common pediatric infections of the middle ear and upperrespiratory tract, as well as certain forms of pneumonia that affectsthe elderly. However, such antibiotics are extremely bitter, and evenwhen dissolved in trace quantities in a liquid dosage form are oftenperceived to be unpalatable. Administration of such antibiotics tochildren and the elderly poses a challenge as these patients experiencedifficulty in swallowing solid oral dosage forms. For these patients,antibiotics are typically provided in liquid forms, such as solutions,emulsions, and suspensions, which usually permit perceptible exposure ofthe antibiotic to the taste bud.

There is a need to mask the taste of such antibiotics in order to ensurepatient compliance during therapy. Conventional taste maskingtechniques, such as the use of sweeteners, amino acids, and flavoringagents often are unsuccessful in masking the taste of highly bitterdrugs and, consequently, other techniques need to be exploited foreffectively masking the taste of these antibiotics.

One such technique involves the use of cation exchange resins, such aspolysulfonic acid and polycarboxylic acid polymers, to adsorb aminedrugs for taste masking and sustained release. However, this techniquehas limited applicability and is not capable of masking the taste ofhighly bitter drugs.

Coating of bitter drugs is another method which has been reported fortaste masking. This technique alone may prove effective for moderatelybitter drugs or in products where the coated particles are formulated asaqueous preparations before administration or are formulated in anon-aqueous medium. This technique has its limitations as coating offine particles is usually technology intensive and coated granules arereadily ruptured by chewing and compression.

Lipid-based microencapsulation is another technique used to taste maskthe drugs. This technique requires highly sophisticated hot-meltgranulation for producing fine particles, and may have adverse effectson heat sensitive molecules or restrict drug release adversely. U.S.Pat. No. 4,865,851 describes cefuroxime axetil in particulate formcoated with an integral coating of lipid or a mixture of lipids.

U.S. Pat. No. 4,808,411 describes a taste-masked composition in the formof granules which contain clarithromycin and a carbomer acrylic acidpolymer. The clarithromycin and carbomer are believed to be heldtogether by both the ionic interactions between the amine group ofclarithromycin and the carbonyl group of the carbomer and by the gelproperties of the carbomer. This complex is further taste masked bycoating.

U.S. Pat. No. 5,286,489 describes a porous drug-polymer matrix formed byadmixing one or more bitter tasting active ingredient and a methylmethacrylic ester copolymer in at least a 1:1 by weight ratio of activeingredient to copolymer, effective to mask the taste of the drug. Noneof the examples described in U.S. Pat. No. 5,286,489 describe the effectof such polymers on the release of the drug from the matrix. While sucha drug-polymer matrix may result in good taste-masking, the matrix mayalso retard the rate of drug release from the matrix to an extent whichwould be unacceptable for a conventional immediate-release formulation.

U.S. Pat. No. 5,633,006 describes a taste-masked composition containinga bitter pharmaceutical agent such as azithromycin, an alkaline earthoxide such as magnesium oxide, and a pharmaceutically acceptablecarrier.

U.S. Pat. No. 6,565,877 describes a taste-masked composition containinga bitter tasting drug, such as clarithromycin, and a combination of twoenteric polymers comprising a methacrylic acid copolymer and a phthalatepolymer, wherein the ratio of methacrylic acid copolymer to phthalatepolymer is between 1:9 or 9:1.

International Application WO 03/082248 describes a pharmaceuticalcomposition containing erythromycin A or a derivative thereof, such asclarithromycin, and alginic agid. International Application WO 03/082241describes a pharmaceutical composition containing micronizedclarithromycin. The clarithromycin has a particle size less than 35microns.

SUMMARY OF THE INVENTION

The invention provides an antibiotic composition comprising coatedmicropellets and optionally one or more excipients, wherein said coatedmicropellets comprise (i) a core comprising at least one antibiotic;(ii) an inner coating comprising at least one cellulose polymer which isnot an enteric coating polymer; and (iii) an outer coating comprising atleast one enteric coating polymer, wherein said coated micropellets havea mean particle size of about 100 μm to about 650 μm.

According to another aspect, the invention provides an oral suspensioncomprising (a) an antibiotic composition which comprises coatedmicropellets and optionally one or more excipients, (b) additionalexcipients, and (c) a solvent, wherein said coated micropellets comprise(i) a core comprising at least one antibiotic; (ii) an inner coatingcomprising at least one cellulose polymer which is not an entericcoating polymer; and (iii), an outer coating comprising at least oneenteric coating polymer, wherein said coated micropellets have a meanparticle size of about 100 μm to about 650 μm.

According to another aspect, the invention provides a method forpreparing an antibiotic composition comprising coated micropellets andoptionally one or more excipients, said method comprising (A) mixing atleast one antibiotic, and optionally one or more excipients, to form apremix; (B) adding a solvent, and optionally one or more excipients, tothe premix formed in Step (A) and granulating in the presence of animpeller set at least at 50 rpm, to form a wet granulation; (C) dryingthe wet granulation, and optionally milling and screening the driedgranules to form micropellets; and (D) coating the micropellets with aninner coating comprising at least one cellulose polymer which is not anenteric coating polymer; and (E) coating the micropellets from Step (D)with an outer coating comprising at least one enteric coating polymer toform coated micropellets, wherein said coated micropellets have a meanparticle size of about 100 μm to about 650 μm.

The oral suspension of the invention is characterized by a lack ofbitter taste.

DESCRIPTION OF THE INVENTION

The invention provides an antibiotic composition comprising coatedmicropellets and optionally one or more excipients, wherein said coatedmicropellets comprise (i) a core comprising at least one antibiotic;(ii) an inner coating comprising at least one cellulose polymer which isnot an enteric coating polymer; and (iii) an outer coating comprising atleast one enteric coating polymer, wherein said coated micropellets havea mean particle size of about 100 μm to about 650 μm. As used herein,“coated micropellets” refers to granules having a mean particle size ofabout 100 μm to about 650 μm, preferably 200 μm to about 500 μm. Morepreferably, at least about 90%, preferably 95%, of the coatedmicropellets have a particle size of about 100 μm to about 650 μm, mostpreferably, about 200 μm to about 500 μm.

Preferred antibiotics include the following: erythromycin;clarithromycin; fluoroquinolones, such as ciprofloxacin and norfloxacin;cephalosporins, such as cefuroxime and ceftriaxone; and tetracyclicantibiotics, for example, chloramphenicol, chlorpromazine, etc. Acombination of antibiotics may also be used. Preferably, the antibioticis clarithromycin. The antibiotic preferably has a particle size ofabout 0.1 μm to about 100 μm, more preferably 5 μm to about 40 μm.

The antibiotic is present in an amount of from about 1 wt. % to about 80wt. %, based on the total weight of the coated micropellet. Preferably,the antibiotic is present in an amount of from about 5 wt. % to about 50wt. %, more preferably, about 20 wt. % to about 35 wt. %, based on thetotal weight of the coated micropellet.

Preferred cellulose polymers include the following: hydroxypropylmethylcellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose,carboxymethylethyl cellulose, sodium carboxymethyl cellulose, andethylcarboxyethyl cellulose. A combination of cellulose polymers mayalso be used. More preferably, the cellulose polymer ishydroxypropylmethyl cellulose or hydroxypropyl cellulose. Mostpreferably, the cellulose polymer is hydroxypropylmethyl cellulose.

Preferred enteric coating polymers include the following: cross-linkedpolyvinyl pyrrolidone; non-cross linked polyvinylpyrrolidone;hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl celluloseacetate succinate, cellulose acetate succinate; cellulose acetatephthalate, hydroxypropylmethyl cellulose acetate succinate, celluloseacetate trimellitate, hydroxypropyl methyl cellulose phthalate;hydroxypropyl methyl cellulose acetate succinate; starch acetatephthalate; polyvinyl acetate phthalate; carboxymethyl cellulose; methylcellulose phthalate; methyl cellulose succinate; methyl cellulosephthalate succinate; methyl cellulose phthalic acid half ester; ethylcellulose succinate; carboxymethylamide; potassiummethacrylatedivinylbenzene copolymer; polyvinylalcohols;polyoxyethyleneglycols; polyethylene glycol; sodium alginate;galactomannone; carboxypolymethylene; sodium carboxymethyl starch;copolymers of acrylic acid and/or methacrylic acid with a monomerselected from the following: methyl methacrylate, ethyl methacrylate,ethyl acrylate, butyl methacrylate, hexyl methacrylate, decylmethacrylate, lauryl methacrylate, phenyl methacrylate, methyl acrylate,isopropyl acrylate, isobutyl acrylate, or octadecyl acrylate, e.g.EUDRAGIT®-L and -S series, such as L100-55, L30D55, L100, S100, L12,5,and S12,5, available from Rohm; polyvinyl acetate; fats; oils; waxes;fatty alcohols; shellac; gluten; ethylacrylate-maleic acid anhydridecopolymer; maleic acid anhydride-vinyl methyl ether copolymer;styrol-maleic acid copolymer; 2-ethyl-hexyl-acrylate maleic acidanhydride; crotonic acid-vinyl acetate copolymer; glutaminicacid/glutamic acid ester copolymer; carboxymethylethylcellulose glycerolmonooctanoate; polyarginine; poly(ethylene); poly(propylene);poly(ethylene oxide); poly(ethylene terephthalate); poly(vinyl isobutylether); poly(vinyl chloride); and polyurethane. A combination of entericcoating polymers may also be used.

More preferably, the enteric coating polymer is selected from acopolymer of methacrylic acid and methyl methacrylate, and a copolymerof methacrylic acid and ethyl acrylate. Most preferably, the entericcoating polymer is poly(methacrylic acid, ethyl acrylate)1:1(EUDRAGIT®-L30D 55 and EUDRAGIT®-L100-55).

It is within the scope of the invention for the antibiotic compositionsto include one or more pharmaceutically acceptable excipients. Examplesof such excipients are binders, diluents, plasticizers, anti-cakingagents, fillers, solubilizing agents, disintegrants, lubricants,surfactants, flavorants, sweeteners, stabilizers, anti-oxidants,anti-adherents, preservatives, glidants, and pigments. A combination ofexcipients may also be used. Such excipients are known to those skilledin the art, and thus, only a limited number will be specificallyreferenced.

Preferred binders include, but are not limited to, starches, e.g.,potato starch, wheat starch, corn starch; gums, such as gum tragacanth,acacia gum and gelatin; and polyvinyl pyrrolidone, e.g., Povidone.Polyvinyl pyrrolidone is a particularly preferred binder.

Preferred plasticizers include, but are not limited to, citric andtartaric acid esters (acetyl-triethyl citrate, acetyl tributyl-,tributyl-, triethyl-citrate); glycerol and glycerol esters (glyceroldiacetate, -triacetate, acetylated monoglycerides, castor oil); phthalicacid esters (dibutyl-, diamyl-, diethyl-, dimethyl-,dipropyl-phthalate), di-(2-methoxy- or 2-ethoxyethyl)-phthalate,ethylphthalyl glycolate, butylphthalylethyl glycolate andbutylglycolate; alcohols (propylene glycol, polyethylene glycol ofvarious chain lengths), adipates (diethyladipate, di-(2-methoxy- or2-ethoxyethyl)-adipate; benzophenone; diethyl- and diburylsebacate,dibutylsuccinate, dibutyltartrate; diethylene glycol dipropionate;ethyleneglycol diacetate, -dibutyrate, -dipropionate; tributylphosphate, tributyrin; polyethylene glycol sorbitan monooleate(polysorbates such as Polysorbar 50); sorbitan monooleate. A combinationof plasticizers may also be used. A preferred plasticizer for use withthe cellulose polymer is polyethylene glycol, such as polyethyleneglycol 600. A preferred plasticizer for use with the enteric coatingpolymer is a combination of triethyl citrate and glycerol monostearate.Preferred fillers include, but are not limited to, microcrystallinecellulose, starch, pregelatinized starch, modified starch, dibasiccalcium phosphate dihydrate, calcium sulfate trihydrate, calcium sulfatedihydrate, calcium carbonate, dextrose, sucrose, lactose, mannitol, andsorbitol. Lactose is a particularly preferred filler.

Examples of disintegrants include:

-   -   (i) natural starches, such as maize starch, potato starch and        the like, directly compressible starches, e.g., Sta-rx® 1500;        modified starches, e.g., carboxymethyl starches and sodium        starch glycolate, available as Primojel®, Explotab®, Explosol®;        and starch, derivatives, such as amylose;    -   (ii) cross-linked polyvinylpyrrolidones, e.g., crospovidones,        such as Polyplasdone® XL and Kollidon® CL;    -   (iii) alginic acid and sodium alginate;    -   (iv) methacrylic acid-divinylbenzene copolymer salts, e.g.,        Amberlite® IRP-88; and    -   (v) cross-linked sodium carboxymethylcellulose, available as,        e.g., Ac-di-sol®, Primellose®, Pharmacel® XL, Explocel® and        Nymcele ZSX.

Additional disintegrants also include hydroxypropyl cellulose,hydroxypropylmethyl cellulose, croscarmellose sodium, sodium starchglycolate, polacrillin potassium, polyacrylates, such as Carbopol®,magnesium aluminium silicate and bentonite.

Examples of surfactants include:

-   -   1) reaction products of a natural or hydrogenated castor oil and        ethylene oxide. The polyethyleneglycol-hydrogenated castor oils        available under the trademark CREMOPHOR are especially suitable,        such as CREMOPHOR RH 40 and CREMOPHOR RH 60. Also suitable are        polyethyleneglycol castor oils such as that available under the        trade name CREMOPHOR EL.    -   2) Polyoxyethylene-sorbitan-fatty acid esters, also called        polysorbates, for example mono- and tri-lauryl, palmityl,        stearyl and oleyl esters of the type known and commercially        available under the trademark TWEEN.        -   20 [polyoxyethylene(20)sorbitanmonolaurate],        -   21 (polyoxyethylene(4)sorbitanmonolaurate],        -   40 [polyoxyethylene(20)sorbitanmonopalmitate],        -   60 (polyoxyethylene(20)sorbitanmonostearate],        -   65 [polyoxyethylene(20)sorbitantristearate],        -   80 [polyoxyethylene(20)sorbitanmonooleate],        -   81 [polyoxyethylene(5)sorbitanmonooleate],        -   85 [polyoxyethylene(20)sorbitantrioleate].        -   A preferred product of this class is TWEEN 80.

Although polyethylene glycol (PEG) itself does not function as asurfactant, a variety of PEG-fatty acid esters have useful surfactantproperties. Among the PEG-fatty acid monoesters, esters of lauric acid,oleic acid, and stearic acid are most useful. Among the surfactants ofTable 1, preferred hydrophilic surfactants include PEG-8 laurate, PEG-8oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate,PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate and PEG-20oleate.

-   -   3) Polyoxyethylene fatty acid esters, for example        polyoxyethylene stearic acid esters of the type known and        commercially available under the trademark MYRJ.    -   4) Polyoxyethylene-polyoxypropylene copolymers and block        copolymers, for example of the type known and commercially        available under the trademark PLURONIC, EMKALYX and POLOXAMER.        Preferred products of this class are PLURONIC F68 and POLOXAMER        188.    -   5) Dioctylsulfosuccinate or di-[2-ethylhexyl]-succinate.    -   6). Phospholipids, in particular lecithins. Suitable lecithins        include, in particular, soybean lecithins.    -   7) Propylene glycol mono- and di-fatty acid esters such as        propylene glycol dicaprylate (also known and commercially        available under the trademark MIGLYOL 840), propylene glycol        dilaurate, propylene glycol hydroxystearate, propylene glycol        isostearate, propylene glycol laurate, propylene glycol        ricinoleate, and propylene glycol stearate.    -   8) Polyoxyethylene alkyl ethers such as those commercially        available under the trademark BRIJ, e.g., Brij 92V and Brij 35.    -   9) Tocopherol esters, e.g., tocopheryl acetate and tocopheryl        acid succinate.    -   10) Docusate salts, e.g., dioctylsulfosuccinate or related        compounds, such as di-[2-ethylhexyl]-succinate.

A combination of surfactants may also be used.

Preferred sweeteners include, but are not limited to, artificialsweeteners such as aspartame, saccharin, and cyclamates; naturalsweeteners such as sucrose, fructose, glucose, lactose, maltodextrin,and sodium glycolate; and mixtures of artificial and natural sweeteners,such as a mixture of aspartame and sucrose.

Preferred flavorants include, but are not limited to, cherry,strawberry, fruit punch, grape, cream, vanilla, chocolate, mocha,spearmint, cola, and the like.

Preferred pigments include, but are not limited to, titanium dioxide,iron oxide, and vegetable dyes.

Preferred diluents include, but are not limited to, dextrose, sorbitol,sucrose, lactose, mannitol, urea, potassium chloride, sodium chloride,gelatin, starch, methyl cellulose, ethyl cellulose, propyl cellulose,hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methyl cellulose, silica, polyvinyl alcohol,polyvinylpyrrolidone, and magnesium stearate.

The antibiotic compositions of the invention are prepared by utilizingany one of a wide variety of different methods well known to one ofordinary skill in the art. The antibiotic compositions are preferablyprepared by mixing at least one antibiotic, and optionally one or moreexcipients, in the presence or absence of a solvent, to form a premix.The premix is preferably in the form of a solid dispersion or ahomogeneous suspension. The premix is preferably subject to high sheargranulation, melt extrusion, wet granulation, or roller compachon, toform micropellets. The micropellets are preferably dried, or cooled inthe case of melt extrusion, and optionally milled and/or screened. Themicropellets are coated with an inner coating comprising at least onecellulose polymer which is not an enteric coating polymer; and an outercoating comprising at least one enteric coating polymer, to form coatedmicropellets.

In the case of high shear granulation, the high-shear granulation ispreferably conducted in the presence of an impeller set at least at 50rpm. More preferably, the impeller is set at about 300 rpm. Mostpreferably, the high-shear granulation is additionally conducted in thepresence of a chopper which preferably is set at least at 1000 rpm, morepreferably the chopper is set at about 2400 rpm.

In one embodiment of the invention, the antibiotic composition isprepared by a method comprising: (A) mixing at least one antibiotic, andoptionally one or more excipients, to form a premix; (B) adding asolvent, and optionally one or more excipients, to the premix formed inStep (A) and granulating in the presence of an impeller set at least at50 rpm, to form a wet granulation; (C) drying the wet granulation, andoptionally milling and screening the dried granules to formmicropellets; and (D) coating the micropellets with an inner coatingcomprising at least one cellulose polymer which is not an entericcoating polymer; and (E) coating the micropellets from Step (D) with anouter coating comprising at least one enteric coating polymer to formcoated micropellets.

Drying techniques include spray-drying, fluid bed drying, flash drying,ring drying, micron drying, tray drying, vacuum drying, radio-frequencydrying and microwave drying. A preferred drying technique is fluid bed.

Types of mills include fluid energy mill, ball mill or rod mill, hammermill, cutting mill and oscillating granulator. More specifically,suitable mills include, Quadro, Fryma, Glatt Quick Sieve, Fluidaire,Fitzpatrick (Fitz mill), BTS mill and Tornado. A preferred mill is aFitz mill. The antibiotic compositions of the invention may be in theform of an oral suspension, capsule, caplet, powder, or tablet. In apreferred embodiment, the antibiotic compositions are in the form of anoral suspension. The oral suspension comprises (a) an antibioticcomposition which comprises coated micropellets and optionally one ormore excipients, (b) additional excipients, and (c) a solvent, whereinsaid coated micropellets comprise (i) a core comprising at least oneantibiotic; (ii) an inner coating comprising at least one cellulosepolymer which is not an enteric coating polymer; and (iii) an outercoating comprising at least one enteric coating polymer, wherein saidcoated micropellets have a mean particle size of about 100 μm to about650 μm. The solvent for the oral suspension is preferably an aqueoussolvent. The oral suspension is generally simply imbibed. Alternatively,the oral suspension may be mixed with foods or drinks.

Examples of additional exciplents are binders, diluents, plasticizers,anti-caking agents, fillers, solubilizing agents, disintegrants,lubricants, surfactants, flavorants, sweeteners, stabilizers,anti-oxidants, anti-adherents, preservatives, glidants, and pigments. Acombination of additional excipients may also be used. Preferredadditional excipients include, sucrose, maltodextrin, potassium sorbate,silica, xanthan gum, titanium dioxide, and a flavorant.

EXAMPLES Example 1 Preparation of a Clarithromycin Composition

Ingredient Amount Clarithromycin 250.0 g Lactose Monohydrate 90.0 gStarch 1500 95.0 g Croscarmellose Na 80.0 g Polyvinylpyrrolidone K-906.0 g Purified Water q.s.

The clarithromycin, lactose, starch and croscarmellose Na were mixed ina 2.5 L high-shear VG5 Glatt granulator for 5 minutes with an impellerset at 350 rpm and chopper set at 2000 rpm. Separately, thepolyvinylpyrrolidone was mixed with water at room temperature untildissolved. The polyvinylpyrrolidone solution was added over a period ofthree minutes to the mixture containing clarithromycin and mixed in thegranulator at 250 mL/min at the above settings. Mixing in the granulatorwas continued for an additional three minutes at the above settings toform wet granules. The wet granules were discharged and placed on a traywhich was placed in an oven at 55° C. for 4 hours to form driedgranules. The dried granules were screened through U.S. Standard SieveNo. 30, 40, 50, and 80 mesh screens. The granules collected on the 30mesh screen were milled using a Quadro Co-mill equipped with a screen#62 to form micropellets. The micropellets were subjected to thescreening procedure as described above and the particle sizedistribution was summarized in Table I. The yield of micropelletsremaining on Sieves Nos. 40 to 80 was determined to be 83.5%, based onthe total amount of ingredients. TABLE I Sieve No. Amount (g) 30 18.6 40207.1 50 136.7 80 49.7 Pan 59.2

Example 2 Preparation of Clarithromycin Composition

Ingredient Amount Clarithromycin 250.0 g Lactose, regular 90.0 g Starch1500 95.0 g Ac-Di-Sol 80.0 g Polyvinylpyrrolidone K-90 6.0 g Water 415mL

The clarithromycin, lactose, starch and Ac-Di-Sol were mixed in a 2.5 Lhigh-shear VG5 Glatt granulator for 5 minutes with a impeller set at 300rpm and chopper set at 2400 rpm. Separately, the polyvinylpyrrolidonewas mixed with water at room temperature until dissolved. Thepolyvinylpyrrolidone solution was added over a period of three minutesto the mixture containing clarithromycin and mixed in the granulator at250 mL/min at the above settings. Mixing in the granulator was continuedfor an additional three minutes at the above settings to form wetgranules. The wet granules were discharged and placed on a tray whichwas placed in an oven at 55° C. for 4 hours to form dried granules. Thedried granules were screened through U.S. Standard Sieve No. 30, 40, 50,and 80 mesh screens. The granules collected on the 30 mesh screen weremilled using a Fitzpatrick Mill equipped with a screen #65 to formmicropellets. The micropellets were subjected to the screening procedureas described above and the particle size distribution was summarized inTable II. The yield of micropellets remaining on Sieves Nos. 40 to 80was determined to be 81.15%, based on the total amount of ingredients.TABLE II Sieve No. Amount (g) 20 4.0 30 57.1 40 120.7 50 179.8 60 29.280 36.0 Pan 45.8

Example 3 Preparation of Clarithromycin Composition

Ingredient Amount Clarithromycin 250.0 g Lactose, regular 75.0 g Starch1500 80.0 g Ac-Di-Sol 80.0 g Polaxomer 188 34.0 g PolyvinylpyrrolidoneK-90 6.0 g Water 400 mL

The clarithromycin, lactose, starch and Ac-Di-Sol were mixed in a 2.5 Lhigh-shear VG5 Glatt granulator for 5 minutes with an impeller set at400 rpm and no chopper blade. Separately, the polyvinylpyrrolidone andPoloxamer 188 were mixed with water at room temperature until dissolved.The polyvinylpyrolidone and polaxomer 188 solution was added over aperiod of fifteen minutes to the mixture containing clarithromycin andmixed in the granulator at 62 mL/min at the above settings. Mixing inthe granulator was continued for an additional three minutes at theabove settings to form wet granules. The wet granules were dischargedand placed on a tray which was placed in an oven at 55° C. for 4 hoursto form dried granules. The dried granules were screened through U.S.Standard Sieve No. 30, 40, 50, and 80 mesh screens. The granulescollected on the 30 mesh screen were milled using a Fitzpatrick Millequipped with a screen #65 to form micropellets. The micropellets weresubjected to the screening procedure as described above and the particlesize distribution was summarized in Table III. The yield of micropelletsremaining on Sieves Nos. 40 to 80 was determined to be 58.0%, based onthe total amount of ingredients. TABLE III Sieve No. Amount (g) 20 36.030 82.5 40 100.7 50 130.6 60 29.2 80 40.0 Pan 57.4

Example 4 Preparation of Clarithromycin Composition

Ingredient Amount Clarithromycin 250.0 g Polaxomer 188 75.0 g

The clarithromycin and Poloxamer 188 were mixed in a container mixerwith a rotation speed of 16 rpm, 5 minutes. The mixture was granulated,by using an extruder Theisson at a temperature of 70° C. The mass wascollected, and cooled down to room temperature. The cooled granules werescreened through a 0.5 mm sieve using an oscilating Frewitt. Thegranules were screened through a 200 μm sieve and collected. The fineparticles <200 μm could be used for a repeated extrusion process.

Example 5 Preparation of Clarithromycin Composition

Ingredient Amount Clarithromycin 704.0 g Polaxomer 188 176.0 gPolyvinylpyrrolidone K-30 120.0 g Water 400.0 g

The Poloxamer 188 and Polyvinylpyrrolidone K-30 were dissolved and mixedin a stainless steel container mixer with stirrer, the clarithromycinwas suspended in this solution. The solution was then spray-dried andagglomerated to pellets in a Glatt GPCG 30—WSA Modul as follows: Spraypressure of sprayguns 2.5 bar Nozzle size 1.5 mm Inlet air temperature110-130° C. Outlet air temperature 65-75° C.

The dried pellets were sieved through a 500 μm sieve. The remainingpellets on the sieve could be re dissolved again.

Example 6 Preparation of Inner Coating (Cellulose Polymer)

Ingredient Amount Hydroxypropylmethyl cellulose 40 g Water 226 mLSimethicone 1 g

Hydroxypropylmethyl cellulose, water and simethicone were mixed.

Example 7 Preparation of Outer Coating (Enteric Coating Polymer)

Ingredient Amount Eugragit L30 D55 419.25 g Polysorbate 80 1.50 gGlyceryl Monostearate 3.75 g Triethyl Citrate 18.75 g Water 306.38 mL

Polysorbate 80, 1.5 g, was dissolved in 250 mL water with heating at 70°C. Glyceryl monostearate, 3.75 g, was added to the polysorbate solutionat 70° C. and mixed. The mixture was allowed to cool with agitation.Eugragit L 30 D55, 419.25 g, which is in the form of a 30% aqueousdispersion was screened through a U.S. Sieve No. 40 mesh screen and theparticles collected on the No. 40 mesh screen were collected. TriethylCitrate, 18.75 g, was mixed with 56.38 mL of water to form a solutionwhich was combined with the Eugragit dispersion, and added to themixture containing polysorbate 80 and glyceryl monostearate, withagitation.

Example 8 Preparation of Coated Micropellets

The micropellets prepared in Example 1,2,3,4,5 were first coated with acellulose polymer coating composition as prepared in Example 6 using aWuster Column in a Glatt Fluid Bed Granulator. The coated micropelletswere further coated with an enteric coating composition as prepared inExample 7 using a Wuster Column in a Glatt Fluid Bed Granulator. Thecoated micropellets were subjected to the screening procedure asdescribed above and the particle size distribution is summarized inTable IV. TABLE IV Sieve No. Amount (g) 30 15.8 40 80.6 50 73.7 60 20.680 20.7 Pan 12.1

Example 9 Preparation of Clarithromycin Oral Suspension Products

Wt. % for 125 mg Wt. % for 250 mg Clarithromycin CompositionClarithromycin Clarithromycin Core Clarithromycin 3.845 7.690 Copolymerof Ethylene 1.003 2.003 Oxide and Propylene Oxide (Polaxomer 188 EP)Polyvinylpyrrolidone 0.683 1.366 (Povidone K-30) Inner CoatingHydroxypropylmethyl 0.600 1.197 Cellulose (Pharmacoat 603) PolyethyleneGlycol 600 0.074 0.151 (Macrogel 6000) Titanium Dioxide 0.178 0.360Outer Coating Poly(methacrylic acid, 2.197 4.391 ethyl acrylate)Eudragit L30D55 Triethyl Citrate 0.329 0.658 Glycerol Monostearate 0.0650.132 (Cutina GMS) Polysorbate 80 (Tween 80) 0.028 0.052 AdditionalExcipients Sucrose 73.846 73.846 Maltodextrin 12.72 3.72 PotassiumSorbate 0.616 0.616 Silicon Dioxide 0.153 0.153 (Aerosil 200) CitricAcid 0.124 0.124 Xanthan Gum 0.153 0.153 Titanium Dioxide 1.076 2.308Fruit Punch Flavor 2.308 1.076 TOTAL 100% 100%

The Poloxamer 188, Povidone K-30, and water were mixed in a stainlesssteel container mixer with stirrer, the clarithromycin was suspended inthis mixture. The mixture was spray-dried and agglomerated tomicropellets in a Glatt GPCG 30—WSA Modul. The dried micropellets weresieved through a 500 μm sieve.

Separately, Pharmacoat 603, Macrogel 6000, and titanium dioxide, weremixed to form an inner layer coating.

Separately, Tween 80 was dissolved in 250 mL water with heating at 70°C. Glyceryl monostearate was added to the Tween 80 solution at 70° C.and mixed. The mixture was allowed to cool with agitation. Eugragit L 30D55, 419.25 g, which is in the form of a 30% aqueous dispersion wasscreened through a U.S. Sieve No. 40 mesh screen and the particlescollected on the No. 40 mesh screen were collected. Triethyl Citrate wasmixed with water to form a solution which was combined with the Eugragitdispersion, and added to the mixture containing Tween 80 and glycerylmonostearate, with agitation to form an enteric coating.

The micropellets prepared above were first coated with the inner coatingusing a Wuster Column in a Glatt Fluid Bed Granulator. The coatedmicropellets were further coated with the enteric coating using a WusterColumn in a Glatt Fluid Bed Granulator. The coated micropellets weremixed with the additional excipients using a V-Blender at 480revolutions to form a clarithromycin powder composition. Theclarithromycin powder composition was placed into a bottle. Water wasadded to the bottle and the bottle was shaken vigorously to form an oralsuspension. The oral suspension is characterized by a lack of bittertaste.

1. An antibiotic composition comprising coated micropellets andoptionally one or more excipients, wherein said coated micropelletscomprise (i) a core comprising at least one antibiotic; (ii) an innercoating comprising at least one cellulose polymer which is not anenteric coating polymer; and (iii) an outer coating comprising at leastone enteric coating polymer, wherein said coated micropellets have amean particle size of about 100 μm to about 650 μm.
 2. The compositionaccording to claim 1, wherein the coated micropellets have a meanparticle size of about 200 μm to about 500 μm.
 3. The compositionaccording to claim 1, wherein at least about 90% of the coatedmicropellets have a particle size of about 100 μm to about 650 μm. 4.The composition according to claim 1, wherein the cellulose polymer isselected from the group consisting of hydroxypropylmethyl cellulose,hydroxypropyl cellulose, methyl cellulose, ethyl cellulose,carboxymethylethyl cellulose, sodium carboxymethyl cellulose,ethylcarboxyethyl cellulose, and combinations thereof.
 5. Thecomposition according to claim 1, wherein the inner coating additionallycomprises at least one plasticizer.
 6. The composition according toclaim 5, wherein the plasticizer is selected from the group consistingof acetyl-triethyl citrate, acetyl tributyl-, tributyl-,triethyl-citrate, glycerol diacetate, glycerol triacetate, acetylatedmonoglycerides, castor oil, dibutyl-phthalate, diamyl-phthalate,diethyl-phthalate, dimethyl-phthalate, dipropyl-phthalate,di-(2-methoxy- or 2-ethoxyethyl)-phthalate, ethylphthalyl glycolate,butylphthalylethyl glycolate, butylglycolate, propylene glycol,polyethylene glycol, diethyladipate, di-(2-methoxy- or2-ethoxyethyl)-adipate, benzophenone, diethyl- and diburylsebacate,dibutylsuccinate, dibutyltartrate, diethylene glycol dipropionate,ethyieneglycol diacetate, ethyleneglycol dibutyrate, ethyleneglycoldipropionate, tributyl phosphate, tributyrin, polyethylene glycolsorbitan monooleate, sorbitan monooleate, and combinations thereof. 7.The composition according to claim 6, wherein the plasticizer ispolyethylene glycol.
 8. The composition according to claim 1, whereinthe enteric coating polymer is selected from the group consisting ofcross-linked polyvinyl pyrrolidone; non-cross linkedpolyvinylpyrrolidone; hydroxypropylmethyl cellulose phthalate,hydroxypropylmethyl cellulose acetate succinate, cellulose acetatesuccinate; cellulose acetate phthalate, hydroxypropylmethyl celluloseacetate succinate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate; hydroxypropyl methyl cellulose acetate succinate;starch acetate phthalate; polyvinyl acetate phthalate; carboxymethylcellulose; methyl cellulose phthalate; methyl cellulose succinate;methyl cellulose phthalate succinate; methyl cellulose phthalic acidhalf ester; ethyl cellulose succinate; carboxymethylamide; potassiummethacrylatedivinylbenzene copolymer; polyvinylalcohols;polyoxyethyleneglycols; polyethylene glycol; sodium alginate;galactomannone; carboxypolymethylene; sodium carboxymethyl starch;copolymers of acrylic acid and/or methacrylic acid with at least onemonomer selected from the group consisting of methyl methacrylate, ethylmethacrylate, ethyl acrylate, butyl methacrylate, hexyl methacrylate,decyl methacrylate, lauryl methacrylate, phenyl methacrylate, methylacrylate, isopropyl acrylate, isobutyl acrylate, and octadecyl acrylate;polyvinyl acetate; fats; oils; waxes; fatty alcohols; shellac; gluten;ethylacrylate-maleic acid anhydride copolymer; maleic acidanhydride-vinyl methyl ether copolymer; styrol-maleic acid copolymer;2-ethyl-hexyl-acrylate maleic acid anhydride; crotonic acid-vinylacetate copolymer; glutaminic acid/glutamic acid ester copolymer;carboxymethylethylcellulose glycerol monooctanoate; polyarginine;poly(ethylene); poly(propylene), poly(ethylene oxide); poly(ethyleneterephthalate); poly(vinyl isobutyl ether); poly(vinyl chloride);polyurethane, and combinations thereof.
 9. The composition according toclaim 8, wherein the enteric coating polymer is selected from the groupconsisting of a copolymer of methacrylic acid and methyl methacrylate,and a copolymer of methacrylic acid and ethyl acrylate.
 10. Thecomposition according to claim 1, wherein the outer coating additionallycomprises at least one plasticizer.
 11. The composition according toclaim 10, wherein the plasticizer is triethyl citrate and glycerolmonostearate.
 12. The composition according to claim 1, wherein theantibiotic is clarithromycin.
 13. An oral suspension comprising (a) anantibiotic composition which comprises coated micropellets andoptionally one or more excipients, (b) additional excipients, and (c) asolvent, wherein said coated micropellets comprise (i) a core comprisingat least one antibiotic; (ii) an inner coating comprising at least onecellulose polymer which is not an enteric coating polymer; and (iii) anouter coating comprising at least one enteric coating polymer, whereinsaid coated micropellets have a mean particle size of about 100 μm toabout 650 μm.
 14. The oral suspension according to claim 13, wherein thesolvent is an aqueous solvent.
 15. A method for preparing an antibioticcomposition comprising coated micropellets and optionally one or moreexcipients, said method comprising (A) mixing at least one antibiotic,and optionally one or more excipients, to form a premix; (B) adding asolvent, and optionally one or more excipients, to the premix formed inStep (A) and granulating in the presence of an impeller set at least at50 rpm, to form a wet granulation; (C) drying the wet granulation, andoptionally milling and screening the dried granules to formmicropellets; and (D) coating the micropellets with an inner coatingcomprising at least one cellulose polymer which is not an entericcoating polymer; and (E) coating the micropellets from Step (D) with anouter coating comprising at least one enteric coating polymer to formcoated micropellets, wherein said coated micropellets have a meanparticle size of about 100 μm to about 650 μm.
 16. The method accordingto claim 15, wherein the granulation is additionally conducted in thepresence of a chopper.
 17. The method according to claim 16, wherein thechopper is set at least at 1000 rpm.